Future Current

The Methuselah Foundation held an informal dinner conversation on October 19 to discuss the effort to secure biotechnological strategies for engineered negligible senescence. Questions were fielded by Aubrey de Grey, Chairman and Chief Science Officer of the Methuselah Foundation. Participants included Jeffrey Hall, Executive Director of SENS, and Allison Taguchi, the Development Officer of the Methuselah Foundation. The event itself was organized by Bruce Klein and Susan Fonseca-Klein of the Immortality Institute.

The following transcript of Aubrey de Grey’s informal October 19, 2007 talk on the Methuselah Foundation and radical life extension has been corrected by the author and approved for publication.

“The only reason that what we do is controversial, really, is because people have this fixation with aging being this sort of mystical thing that is somehow for unspecified reasons outside the ambit of medical intervention. That is why I mention the concept of ‘demystifying aging’ on a biological level.”

The Effort to Postpone Frailty Indefinitely

It’s become clear to me over the past several years that the main difficulty that exists in getting this research really moving fast and getting people sufficiently interested to help to sponsor it is really that the number of people who are actually interested in it is still rather small, and therefore the interaction between those people is insufficiently high bandwidth, so to speak, to actually progress to a point where it becomes self-sustaining. In a town like this, where there is so much technical expertise and love of technical progress, it is an ideal scenario to try to amplify the communication that can exist between people who might not have necessarily ever have met or at least never have met in this sort of context. In a room like this we can have, even with twenty people, more or less one conversation about all of the topics: the science, the social context, and getting people to understand that there is a lot of detail in all this now. We have come to the point where we can engage in the rational design of interventions that may genuinely defeat aging, not just pick away at the edges of it.

It is something that people have a lot of trouble getting used to. Even technically very sophisticated people, not the least biologists, have a hard time getting their head around the idea. The more that we can do in the Methuselah Foundation to demystify aging, to get people to think about it appropriately as a repair and maintenance problem that is becoming increasingly amenable to technological intervention, the faster we will actually be able to put together the research that needs to be done.

Audience: How much money is currently in the Mprize?

Let me take one step back. Some of you might not know quite what the Methuselah Foundation is. It’s a 501(c)(3) that I founded jointly with a businessman in Virginia named Dave Gobel back in 2002. We started off simply having one real initiative that the Methuselah Foundation was involved in, which was to administer and promote this thing called the Methuselah Mouse Prize that we now call the “Mprize.” Essentially the Mprize was a way of simply stimulating and raising the profile of life extension research in a manner that wouldn’t trivialize it. Most non-scientists, as you all know, don’t like to think about science very much. It sends them to sleep. Talking about world records is a different matter entirely. We offered money to people who could make unprecedentedly long-lived mice, and it worked. We have succeeded in getting a lot of prestige for the prize and for the work that is being done in the attempts to extend the lifespan of mice. There is a reasonable amount of money actually being given to us. We started off just with a nominal sum of $5000. It’s now $4.5 million.

But the big answer to that question is how much money we have in the research fund, which is something that we do not just accumulate but we actually spend on research. We’ve got about the same amount. The research fund has recently gone above the prize fund, but of course we’re spending it as fast as we get it in. That money is not all in the bank because a lot of it is pledges. In particular, over half of it is the big pledge that we got from Peter Thiel about a year ago, where he said that he would give us up to $3 million if we were able to get up to $6 million from other people. We are working very hard, of course, to make that happen. The fact that that challenge is out there has an enormous advantage. The fact that we’re a 501(c)(3) in the first place means that people can get tax back, but if they know their donation is going to be augmented by 50% then that’s a considerably greater incentive to contribute to this work.

Audience: How many researchers are funded at the moment?

At the moment we are funding about a dozen people, of whom about four or five are full-time and the rest are part-time. That’s great. It means two of the major components of the seven-point plan that I have been promulgating over the past several years are being pushed forward much faster than they would be if we didn’t exist. But, of course, it’s not nearly enough.

Audience: They’re focused on the problem of the accumulation of junk inside cells?

That’s right. There’s also a separate problem of the accumulation of junk outside cells, which is actually going rather better. There is a company based in south San Francisco called Elan Pharmaceuticals which is focused on the problem of extracellular junk in Alzheimer’s disease. It’s an important problem in other areas, and that’s actually not really being addressed by anybody at the moment. For example, different types of extracellular junk accumulate in Type 2 diabetes in the pancreas, and seem to accelerate the death of islet cells in Type 2 diabetes. It’s also been found recently that people who live to exceptional ages, to 110 or more, when they die a few of them have had autopsies done on them now, and it turns out that a large proportion of them have problems of extracellular, indigestible junk in their hearts. This was a problem that was known to exist, but it was never realized to be nearly so prevalent in the extreme elderly. Again, this is a problem that ought to be addressed in the sort of way that the junk in Alzheimer’s disease is being addressed by Elan and their collaborators, but nobody’s actually working on it. So that’s another thing that we want to put money into when we get it.

Audience: What are you doing in China?

What am I doing in China? I’m speaking at the Asian Congress of Gerontology and Geriatrics, which doesn’t sound very promising really, does it? I have no idea what’s going to happen. It will be my first time in China. But I have been invited by a couple people who are on the organizing committee and who have a lot of interest in my work. They have been talking to me a lot over the past year or two or three. I’m optimistic that they are going to be able to connect me with a bunch of people who will be able to promote this general cause in China. There’s a good reason to believe that in the next five or ten years China will be a major player in this, not just for the usual reasons that they’re a growing economy and they’re interested in biotech and so on, but also because of the specific reason that they have the world’s worst population aging problem. The One-child Policy is biting them in the ass in a big way right now because they’re ending up with a situation where they have increasing prosperity and increasing healthcare for the elderly, which is keeping people alive for longer in an unhealthy state, often. And yet, at the same time, they’ve got this extraordinary shortage of working-age population. So they’ve got an immense economic problem coming. This is clearly already being recognized. The question is, what are they going to do about it? Of course, if they can keep their elderly healthier and less expensive, even to some extent in the workforce, then they’re going to be in a much better situation. They could be very interested indeed in helping this sort of thing happen sooner rather than later.

Audience: If they were to kill off their elderly at a more rapid rate, wouldn’t that also solve their problem?

It would, but for reasons that I have not yet explored they don’t seem to be keen on that.

Audience: The problem is, can you actually make a convincing case that the senescence after the healthy lifespan will be short? If you extend healthy lifespan to 110, followed by 20 years of decrepitude, that doesn’t solve your problem.

It actually still alleviates the problem a little bit, of course, because the proportion of life is reduced. If you’re having the same amount of unhealthy life at the end of a larger amount of healthy life, that’s still better. But only just a bit better.

Audience: Now we have someone without any grandchildren to look after them.

So you’re asking a very important question, because a large part of what I try to do is to emphasize that the compression of morbidity, the idea of actually keeping someone alive for a longer period in a healthy state, followed by a shorter period of unhealth before they die, is biologically implausible. The only way that we are going to be able to actually cause a big shock diminution in the number of frail people is by postponing the age of frailty indefinitely, by actually postponing it into the future faster than time is passing.

Audience: Your so-called “escape velocity.”

That’s right. So that people just never reach this point. They live long enough that the chance of dying by being hit by trucks and stuff like that is high enough that they don’t need to worry about aging.

Audience: It’s a harder sell.

Well, it’s a more complicated sell. Ultimately, it’s a coherent argument, and so one has to just give it in a concise and succinct way.

Audience: I have a question. What is different about what the Methuselah Foundation seeks to achieve apart from what mainstream gerontology is undertaking?

There are two ways to answer your question. The direct question you’ve asked is in regards to the goal, and the related question is in regards to the method of achieving the goal. With regard to the goal, there is no difference. We are interested in alleviating health conditions and suffering. The life extension business is just really a side benefit. It’s just that if you alleviate health conditions really, really comprehensively then people aren’t going to die so often. The only reason that what we do is controversial, really, is because people have this fixation with aging being this sort of mystical thing that is somehow for unspecified reasons outside the ambit of medical intervention. That is why I mention the concept of “demystifying aging” on a biological level.

Audience: What is the difference between the standard research methods and what you do?

That comes to the second question that I just described. The thing about age-related diseases is they’re recognizably bad, but the focus of each community who’s working on a particular age-related disease is on only that disease. So they think in terms of, if they could postpone death from, let’s say cancer, by ten years, that would be a massive triumph. They would reduce the proportion of people that were dying of cancer by a large amount. But the only reason they would do so is because the proportion of people who would have died of cancer will die of something else first. This means that the disease-specific focus of that mindset is a real problem. It means that people are thinking that they have really important solutions to problems, when in fact they’ve only got things that might postpone actual frailty of any sort added together by a very small amount. If you take all of these diseases together, plus the things that we don’t even call diseases, things like the weakening of the immune system and so on, and you were to apply therapies to all of them, then you would need better therapies.

At the level of understanding these diseases, there is no difference between what we do and what mainstream medical people do in characterizing what is actually going wrong. The big difference comes at the level of actually doing something with that understanding. One thing that is going to be different is at the level of intervention. So what I was trying to describe a moment ago was that interventions that would be adequate if you were just focusing on one disease and you were sort of making the default presumptions that no progress was going to be made on all the other diseases, which is what people genuinely do, then you’re going to aim much lower. You’re not going to aim for things that are really going to fix the problem properly. If you actually look at the sort of things that we talk about and we want to promote, these would be regarded by disease-specific thinkers as unnecessarily ambitious.

Then is the role of the Methuselah Foundation to be a lobbyist within medicine?

That is certainly one of our roles. We seek to emphasize that it is counterproductive to consider aging as in some way separate from age-related diseases. It is biologically ridiculous to say that. Ultimately, age-related diseases are simply the later stages of aging. Alternatively, aging is the collective early stages of the diseases. If one thinks about it that way, then one can get much more comfortable with the synergy between the different approaches to fixing these diseases. One can get comfortable with the idea that the fixing of the various precursors of the diseases, the molecular and cellular changes that go on throughout life, will have multifarious preventative effects on many different diseases at the same time. Therefore, we will have much more bang for the buck.

Audience: So, to be clear you’re not looking for a silver bullet?

No, certainly not.

Audience: Seven silver bullets.

Audience: What is happening with Mito-SENS?

What’s happening with Mito-SENS? It’s going very nicely. It just started going much better. Essentially, it’s the idea of making the mitochondrial DNA unnecessary, and therefore making mutations in the mitochondrial DNA harmless. It’s an idea that’s been around for about 20 years, well before I came along, but after a short period of quite promising success, it really ran into the sand and became a bit of a backwater. I think I can claim some credit for getting the relevant research community more interested in it again and pointing out that the problems that had been perceived as real show-stoppers were not that at all. But now we’re in a position where we are actually funding some of the work. The idea here is that mitochondria of course are really important parts of cells. They are essentially the machines that do the chemistry of breathing, the combining of oxygen with nutrients to make carbon dioxide and to extract energy. They have their own DNA. But the DNA is extremely small. It only encodes thirteen proteins, as opposed to the many tens of thousands of proteins encoded by the chromosomes. It turns out not to be completely ridiculous that we might be able to relocate these thirteen genes from the mitochondria into the chromosomes in such a way that they would still work.

Basically, this is an idea that I have been looking at for over a decade now, but that we are now seeing a lot of acceleration of success in. There was one really massive breakthrough this past year from a group in Paris that showed how to overcome the main problem with doing this, which is that the proteins in question after they’ve been synthesized need to be re-imported back into the mitochondria. Essentially, these particular proteins are really resistant to being processed by the machinery in the mitochondrial membrane that normally does this for a thousand other proteins. There has been a discovery of how to get around that problem and we are aggressively funding that group. It’s the only group in the world who has been working on this problem as their main research focus.

Audience: You can design this new genome but how do you start the thing off?

It’s not really a new genome. The mitochondrion is this really complicated machine with over a thousand different proteins in it, nearly all of them already encoded in the nucleus. So it’s really just a case of putting copies of the same gene, suitably modified, into the nucleus. From the point of view of the mitochondrion, it doesn’t matter where the proteins come from. The point is, they’re getting into the mitochondrion and then they’re going to work. Another good thing about all this is that stoichiometry doesn’t matter very much. It’s a back-up thing. If you’re making a bit too much of some of the proteins, the mitochondrion copes. It’s pretty relaxed about how much of these things you can make. So the idea is essentially you just have enough of the stuff coming from somewhere. One problem that one might have expected to be important in this is that mutation in the mitochondrial genome might cause not no proteins but the production of toxic proteins that interfere with the process. But that turns out not to be a problem, because in normal aging the overwhelming majority of mutations that actually accumulate turn out to be mutations that knock out completely all of the protein synthesis process, so that all thirteen proteins are simply not made at all. So it’s all looking very promising.

Audience: Do you have any research to show what percentage of various age-related diseases are a result of damage to mitochondrial DNA?

Very good question. If you go through the seven-point SENS plan, then for all of the other six components there are clear cases where a particular age-related pathology is predominantly caused by some example of that particular category. Cell loss and Parkinson’s disease, no question. Parkinson’s disease is caused by the death and non-replacement of cells in one particular part of the brain, the substantia nigra. Atherosclerosis is definitely caused by the accumulation of indigestible cholesterol variants in cells in the artery wall. Mitochondrial mutation is one exception where we cannot point to any particular age-related problem and say it is driven by the accumulation of mitochondrial mutations. The big deal with SENS is we want to be conservative about what we address. In other words, we want to address everything that might matter, not just say “This definitely matters, therefore let’s address it.”

An awful lot of time has been wasted in gerontology with trying to prove or disprove this or that theory of aging, which basically means trying to establish some sort of pecking order of the importance of different components of the aging process on the eventual outcome, namely the various pathologies of aging. Who gives a damn? The fact is these things all probably matter. And if in fact we find out that a few of them don’t and we fix a few things that we didn’t need to fix, then who cares? No harm done, really. Whereas, if we just prevaricate and waste our time trying to figure out what matters and what doesn’t, then we’re not getting on fixing anything. That’s the situation that gerontology has rather been in for a long time. So, I figure, let’s just fix this particular problem, even though there is no actual hard-and-fast proof that it really matters.

The reason why we’re focused on these two particular things first, lysosomal enhancement (or in other words the elimination of indigestible molecules) and mitochondrial mutations, is because they have a big bang for the buck in credibility terms. The lysosomal enhancement project is one of the two components of the seven-point plan that were completely my idea. The approach that we are using is very radical, bringing in technology that had never been used for anything biomedical before, let alone aging. So that really is a way of demonstrating that there is value in thinking seriously out of the box in how to address these various things. In the case of mitochondrial mutations, the idea that they are important in aging is already established, even though there is no proof of the idea. The general concept has been around for probably 35 years, that mitochondrial mutations are an important driving force in a lot of aspects of aging. And there is plenty of circumstantial evidence for it, which means that what one can do there is address a different aspect of the credibility problem of combating aging. One can address the feasibility, rather than the creativity aspect. Everyone knows what they’d like to do. They would like to make the mitochondrial DNA unnecessary. But everyone says, “Well, that’s far too hard.” So I come along and say, “Well, maybe it isn’t.”

The particularly good thing about mitochondrial manipulation is that the things that people think are hard are the really fundamental things that you can actually demonstrate solutions to in vitro. You don’t even have to get as far as mice to be able to really turn upside down people’s skepticism and cynicism about this particular area. Whereas most of the other things people say, “Yeah, you’ll get it working in cells, and you might even get it working in mice, but you’ll never get it working in humans.” And, of course, you can’t answer that question for many years from now. That’s certainly the reason we chose, in discussion with Peter Thiel who is funding it, that particular strand of SENS as a good one to start with for ramping up the credibility of the whole thing.

Audience: You won’t be able to answer, “How much longer will people live now?”

You don’t need to answer that.

Audience: The old mouse you can put on TV as a demonstration that it works.

That’s a little further along. In the first instance, we’re interested in legitimizing the SENS approach to this whole problem as much as possible before we get the mice. In the next couple of years we want people to be able to go and write their own grants to other perfectly traditional funding agencies to get these things funded because they are realistic.

Audience: What if there’s a reason those thirteen proteins stayed outside the nucleus?

Oh, well, we know there is a reason from an evolutionary point-of-view. We know that this business of the hydrophobicity, the fact that the things are not well processed by the protein input machinery is a fine reason.

Audience: There are lots of different mitochondria and I gather that different proteins in different species have been migrated into the nucleus. Is that not the case?

Excellent question. So, in fact, the first time that I actually succeeded in getting people to do experiments that they weren’t doing otherwise just by embarrassing them into it was based on exactly the point you just made. There is a type of algae that is worked on a lot in biotechnology, Chlamydomonas reinhardtii, that only have seven of the thirteen proteins in their mitochondrial DNA. This was discovered back in 1990, the sequence of the mitochondria of this species. I got into this in like ’97 and I discovered this, and I immediately thought, well, obviously people will then have gone and cloned these things out of the nucleus, because you can’t just lose these things, the enzymes are too conserved. You’ve got to have the genes, they’ve got to be there. And, I found that nobody had. Nobody had just got round to that. So I got up on stage, probably my third ever invited talk, in early 1998, and basically berated my audience for not having got around to it. And someone in the audience that I had never met before, but was a very top mitochondriologist, rather took it seriously and went and forged a collaboration with some people who had never worked with mitochondria but had studied Chlamydomonas. That collaboration was extremely productive. Very quickly we did indeed find stuff out about how these genes are succeeding in getting in, basically by the loss of hydrophobicity, so it was extremely productive. That was very important.

However, it turns out that the phenomenon you describe of different species having different things is not as widespread as you would think. All animals have exactly the same thirteen, except one gene has probably genuinely been lost, a very small one in some species, particularly Caenorhabditis elegans. Apart from that one case, there seems to be complete uniformity. A large part of the reason is because of the genetic code. Mitochondria, as most of you already know, originated in what is called an endosymbiotic event, where a cell that didn’t have a mitochondrion at all yet engulfed a free-living bacterium. After that, most of the genes were very rapidly lost or transferred to the nucleus. It was, as I say, a very rapid process. We see species that have still got maybe a hundred proteins encoded in their mitochondrial DNA, but once it went down to like fifteen or so, it became easier for mutations to alter the genetic code. What you see in the mitochondria of animals now is that out of the 64 different three base pair codons that define an amino acid, four of them actually don’t encode the same thing in the mitochondrion that they do in the nucleus. There is one particular codon, UGA, which encodes stop (end of the protein) in the nucleus but it encodes an amino acid in the mitochondria. This is the kiss of death to transfer of mitochondrial DNA. Essentially what happens is that if a gene is transfered from the mitochondrial DNA now to the nucleus, then it will encode a truncated protein. So it is completely now impossible for evolution to succeed in moving these things. But of course rewriting that aspect of the genetic code is not a big deal anymore, is a trivial thing for us to do. You can make site-directed mutations in DNA sequences very easily in the lab.

The big breakthrough that was made by this group in Paris, it had been known for about 35 years that some mitochondrial proteins that are already naturally nuclear-coded are in fact synthesized on the outer surface of the mitochondria. So, it has been known for a long time that the way that mitochondrial proteins are identified is by a leader sequence, a few amino acids at the beginning of the protein that say “This is a mitochondrial protein.” That gets identified and the protein gets dragged into the mitochondrion and imported. So that’s very good. But this particular phenomenon is where the actual messenger RNA, which is the intermediary between the DNA and the protein, itself gets translocated to the mitochondrion, and it does not get imported. It just gets transported to the outside of the mitochondrion. But that’s good enough, because then the synthesis of the protein actually occurs on the surface of the mitochondrion and the importing of that protein inside of the mitochondrion can actually happen while the protein is in the process of being synthesized. Now, this is fantastic, because the problem with importing these really nasty proteins into the mitochondrion is they fold up into a globule and they don’t like to unfold. The actual machinery that imports proteins into the mitochondrion needs to unfold the protein as a precursor to being able to get it in. So, if it can be done while the thing is being synthesized, then the folding up hasn’t happened yet, and you basically sidestep the whole problem.

Originally this was discovered just for a few proteins way back 30 years ago. The big discovery that the Parisian group made was that there is actually a much wider range of proteins being done this way. In particular, they found a few that are being done very faithfully this way. Basically every single protein gets done in this way. That’s great, because it means that you can potentially take some parts of the sequence of these genes and attach them to the protein-coding sequence of the genes of interest, the ones that are normally in the mitochondrial DNA. The good news is that the parts of the gene that you have to attach are not the coding parts. The 3′ untranslated region, in other words the back end of the messenger RNA, is the part that you have to address. Well, the beginning as well, but essentially that seems to work. Now, if this is such a neat way of getting genes to get into the mitochonrion, then shouldn’t have evolution have done it? So, I mentioned this business about the change in the genetic code. Once that happens then there is no longer any pressure to do any other tricks, because you can’t do that trick. The big thing also is that the more hydrophobic a protein is, the more faithfully this has to happen. So it could be that 80% of the protein is synthesized on the surface, but 20% is synthesized on the body of the cell, and that would be quite bad enough.

Audience: Can this be done for all of your cells at the same time?

I’m hoping that it can be done. Essentially because we are talking about introducing genes into the nuclear genome, we can use standard somatic gene therapy. Now, of course, we’re not very good at gene therapy yet, you may have noticed. But we’re getting better. And we’re already really pretty good at it in mice. The big problem that gene therapy has had, of course, is the safety problem. If you kill one person in a big trial then that sets gene therapy back by a year. That doesn’t happen if you kill one mouse. So I’m pretty hopeful that gene therapy is moving forward fast enough that we will be able to get these genes into us, not into every single cell of course, but you don’t have to get it into every single cell. Just into a good majority of cells by the time we’ve figured out how to modify the genes in the appropriate way so that we know what to get in in the first place.

The other problem, however, mutant mitochondrial DNA seems to be preferentially proliferated. So if you’ve got a cell with ten thousand mitochondrial genomes, you would think that’s great because you’ve got lots of redundancy, it doesn’t matter if you have a few that are mutated. It turns out that actually, no, having a lot of genomes is part of the problem, because if any of them mutate then they have a chance of becoming clonally expanded, enjoying for whatever reason a proliferative advantage, and the mechanism for this is still not known, though I proposed one about ten years ago in my first paper in this area.

Audience: Intracellular mitochondrial leukenmia, basically?

That’s exactly it. Basically, any mutant that gets away takes over the whole cell, at the expense of the working mitochondrial DNA. That means that the functional mutation rate, the rate of the actual abundance of mutations, is many orders of magnitude higher in mitochondrial DNA than in nuclear DNA.

Audience: How will you eliminate the mitochondrial DNA from the cells after you have made it nuclear?

There are ways, but we probably won’t need to. The mutant mitochondrial DNA tends to be deleted in such a way that it doesn’t actually make any proteins at all, so it does not get in the way. In a cell that has its mitochondrial DNA intact, you’re going to be making more protein than you need of these thirteen relative to the others, but that doesn’t seem to be a problem. There is an awful lot of slop in the stoichiometry.

Audience: The one that mutates, as you say, manages to spread itself out more effectively than a mutation in the nucleus.

Well, first of all, the mechanism for that probably has to do with the dysfunction of the mitochondrion. If the mitochondrion is no longer dysfunctioning as a result of the mutation because it’s getting its proteins from elsewhere, then that probably won’t happen. But also, even if that’s not the mechanism of amplification, so what if it’s amplified. It’s not going to do any harm, anyway. The proteins are being made from the nucleus.

Continued in “The Task of Arguing for Extended Life“

 

This entry was posted on Tuesday, October 23rd, 2007 at 9:31 pm and is filed under Aubrey de Grey, Life Extension, SENS. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.